APOL1 studies in kidney transplantation consortium clinical centers (ASK-CCC)

摘要

ABSTRACT The ever-widening gap between the need and availability of kidneys for transplantation remains a major challenge to the goal of transplanting all whom may benefit from it. The kidney transplant waiting list is further burdened by patients seeking a repeat transplant due to premature transplant loss. Given this mounting challenge, it is imperative that we use the limited available kidneys more efficiently by matching recipient and transplant organ longevity and by minimizing discard of marginal kidneys that could be used in better suited patients. The Kidney Donor Profile Index provides an estimate of kidney quality and African American (AA) donor race is a variable associated with poorer outcomes. In the general population, AAs are more likely to develop chronic kidney disease (CKD) than individuals of other races. Recent observational studies suggest that high- risk APOL1 genotype variants (HR-APOL1), found exclusively in AA, accounts for 70% of this increased risk. Only a subset of AAs carrying HR-APOL1 develop CKD. In transplantation, recent studies and our preliminary data suggest that kidneys from AA donors with HR-APOL1 are at a greater risk for graft loss compared to donors with low risk APOL1 variants (LR-APOL1). Similar to APOL1-asscoiated CKD, only 20-30% of HR-APOL1 kidneys fail within 2 to 3 years of transplant. It appears that HR-APOL1 genotype alone does not predispose to graft loss but in the presence of a “second hit” they fail prematurely. At the same time, recent data suggests that AA live kidney donors are more likely to develop CKD than non-AA donors. It is possible that AA living kidney donors carrying HR-APOL1 are at increased risk for post-donation CKD. To further elucidate the role of donor APOL1 on recipient graft and living donor outcomes we propose to assemble a cohort of kidney transplant recipients, from living or deceased donors with African ancestry and address the following specific aims: 1) We will determine if either HR-APOL1 genotype in the donor kidney or the recipient associates with greater kidney transplant function decline and graft loss when compared to recipients of LR-APOL1 kidneys; 2) To collect longitudinal clinical data and biological samples from AA donor kidney transplant recipients to evaluate transplant related immune- and non-immune “second hit(s)” candidates that trigger early graft dysfunction and failure in recipients of kidneys from HR-APOL1 donors; and 3) To prospectively collect pre- and post-donation clinical and laboratory data from AA living kidney donors to determine if HR-APOL1 genotype associates with lower pre- donation kidney function and greater post-donation kidney function decline, and albuminuria compared to LR- APOL1 donors. Our consortium is ideally positioned to undertake this study as it brings together a large cohort of study participants, including Caribbean-Latinos, a group of investigators with complementary expertise, and state-of-art research facilities. Determining the impact of donor APOL1 gene variants on recipient and donor outcomes will improve our ability to care for this population.